Polymorphic clopidogrel hydrogenesulphate form

ABSTRACT

Novel orthorombic polymorph of clopidogrel hydrogen sulfate or hydrogen sulfate of methyl (+)-(S)-alpha-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-acetate and a process for its preparation.

The present invention relates to a novel polymorph of clopidogrelhydrogen sulfate or the hydrogen sulfate of methyl(+)-(S)-α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-acetateand a process for its preparation. More particularly, the inventionrelates to the preparation of this polymorph called Form 2 and to theisolation of this compound in this novel crystalline form, as well as topharmaceutical compositions containing it.

Clopidogrel hydrogen sulfate is a platelet aggregation inhibitor whichwas described for the first time in EP 281459. The synthetic processclaimed in this patent leads to the preparation of clopidogrel hydrogensulfate which is called Form 1. It has now been discovered thatclopidogrel hydrogen sulfate can exist in different polymorphiccrystalline forms which differ from each other by their stability, theirphysical properties, their spectral characteristics and the process fortheir preparation.

Thus, one of these novel polymorphic forms is the object of the presentinvention, it is described in the present application and will be namedForm 2.

The present invention also relates to a process for the preparation ofclopidogrel hydrogen sulfate in its polymorphic Form 2.

Patent EP 281459 describes enantiomers of tetrahydrothienopyridinederivatives and their pharmaceutically acceptable salts. EP 281459specifically claims clopidogrel hydrogen sulfate, i.e. thedextrorotatory isomer which possesses an excellent platelet aggregationinhibiting activity whereas the levorotatory isomer is less active andless well tolerated. Patent EP 281459, filed ten years ago, makes noreference to the existence of specific polymorphic forms of clopidogrelhydrogen sulfate. The synthesis described in EP 281459 leads to thepreparation of the hydrogen sulfate of the polymorph of clopidogrelForm 1. Nor does EP 281459 suggest the existence of differentpolymorphic forms of clopidogrel or of clopidogrel hydrogen sulfate.

According to all of the teachings of the above documents, thedextrorotatory isomer of clopidogrel is prepared by salt formation fromthe racemic compound using an optically active acid such as10-L-camphorsulfonic acid in acetone, followed by successiverecrystallisations of the salt until a product with constant rotatorypower was obtained, followed by release of the dextrorotatory isomerfrom its salt by a base. Clopidogrel hydrogen sulfate is then obtainedin a standard manner by the dissolution of said base in acetone cooledin ice and addition of concentrated sulfuric acid to precipitation. Theprecipitate thus obtained is then isolated by filtration, washed anddried to give clopidogrel hydrogen sulfate in the form of white crystalswhose melting point is 184° C. and optical rotation +55.1°(c=1.891/CH₃OH).

The process described in the prior art leads only to the form 1 ofclopidogrel hydrogen sulfate.

Thus, the present invention relates to the polymorphic form called Form2 of clopidogrel hydrogen sulfate which, like Form 1 of this compound,is useful as a medicine for prophylaxis and the treatment of thrombosisby acting as a platelet aggregation inhibitor. As far as the use ofclopidogrel and its salts is concerned, reference may be made to Drugsof the Future, 1993, 18, 2, 107-112. Polymorphic Form 2 of clopidogrelhydrogen sulfate is thus used as active ingredient for the preparationof a medicine, in combination with at least one pharmaceuticallyacceptable excipient, in the same indications as Form 1.

It has now been found that if clopidogrel hydrogen sulfate iscrystallised from a solvent, either the crystalline form, Form 1,corresponding to that of the product obtained according EP 281459mentioned above may be produced or a new, very stable crystalline formhaving a well-defined structure designated Form 2 below. Moreparticularly, it has been found that the novel crystalline form ofclopidogrel hydrogen sulfate, Form 2, is at least as stable as the Form1 described and that it does not convert spontaneously into thepreviously known Form 1. Furthermore, Form 2 bulk solid is more compactand much less electrostatic than Form 1 and may hence be more readilysubjected to any treatment under the usual conditions of pharmaceuticaltechnology and, in particular, of formulation on an industrial scale.

It has moreover been observed that Form 2 exhibits a lower solubilitythan Form 1 as a result of its greater thermodynamic stability.

The difference between the new crystalline form of clopidogrel hydrogensulfate according to the present invention, Form 2, and Form 1 isapparent on examination of the FIGS. 1 to 4, whereas the FIGS. 5 to 7demonstrate the structure in the crystals of Form 2.

The FIGS. 1 to 7 are characterised as follows:

FIG. 1 gives the X-ray powder diffractogram of clopidogrel hydrogensulfate Form 1;

FIG. 2 shows the X-ray powder diffractogram of clopidogrel hydrogensulfate Form 2;

FIG. 3 shows the infrared spectrum of Form 2;

FIG. 4 shows the infrared spectrum of Form 1;

FIG. 5 shows the structural formula of clopidogrel hydrogen sulfate withthe numbering of the atoms in the crystalline Form 2;

FIG. 6 shows the spatial conformation of Form 2 clopidogrel hydrogensulfate;

FIG. 7 shows the stacking of the molecules of Form 2 clopidogrelhydrogen sulfate in the unit cell of the crystal.

It was observed from the crystallographic data that the crystallinestructure of Form 1 contains two crystallographically independentcations of clopidogrel and two independent bisulfate anions. The twoindependent cations are of similar conformation.

The crystallographic data of Form 2 show that it contains onecrystallographically independent clopidogrel cation-bisulfate anionpair.

In the two forms, the cations are protonated axially and the nitrogenatom has the R configuration; the conformation of the cations in Form 2is different from that observed in Form 1.

No site is occupied by solvent molecules in the molecular arrangement ofthe two crystalline forms.

The arrangement of the anions is very different in the two crystallinestructures. The crystalline structure of Form 2 (orthorhombic) is lessdense (1.462 g/cm³) than the crystalline structure (monoclinic) of Form1 (1.505 g/cm³).

According to another feature, the object of the present invention is aprocess for the preparation of Form 2 of clopidogrel hydrogen sulfatewherein:

(a) methyl(+)-(S)-α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-acetatecamphorsulfonate is suspended in an organic solvent,

(b) the camphorsulfonic acid is extracted with an aqueous alkalinesolution of potassium carbonate and the organic phase is washed withwater,

(c) the organic phase is concentrated in a vacuum and the concentratedresidue is taken up in acetone,

(d) 80% sulfuric acid is added,

(e) the mixture is heated to reflux, the product crystallises, themixture is cooled, filtered and the crystals are washed, then driedunder reduced pressure to give clopidogrel hydrogen sulfate Form 1,

(f) the resulting mother liquors, yield after a 3 to 6 months periodcrystals of clopidogrel hydrogen sulfate Form 2.

Furthermore, the invention concerns a process for the preparation of(+)-(S) clopidogrel hydrogen sulfate Form 2 wherein:

the resulting mother liquors of crystallisation of Form 1 of (+)-(S)clopidogrel hydrogen sulfate yield after a 3 to 6 months period crystalsof clopidogrel hydrogen sulfate Form 2.

The resulting hydroacetonic mother liquors of crystallisation of Form 1of (+)-(S) clopidogrel hydrogen sulfate contains from 0.3 to 1% ofwater.

Those mother liquors contains until more or less 10% of clopidogrelhydrogen sulfate, this amount being calculated on the bases of theammount of methyl(+)-(S)-α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-acetatecamphorsulfonate used for the transformation into hydrogen sulfate.

The mother liquors yield slowly after a 3 to 6 months period, at atemperature below 40° C., clopidogrel hydrogen sulfate Form 2.

According to another of its features, the present invention relates toanother process for the preparation of Form 2 of clopidogrel hydrogensulfate wherein;

(a) methyl(+)-(S)-α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-acetatecamphorsulfonate is suspended in an organic solvent,

(b) the camphorsulfonic acid is extracted with an aqueous alkalinesolution of potassium carbonate and the organic phase is washed withwater,

(c) the organic phase is concentrated in a vacuum and the concentratedresidue is taken up in acetone,

(d) 96% sulfuric acid is added at 20° C. and the solution is seeded withclopidogrel hydrogen sulfate Form 2,

(e) the product crystallises, the mixture is cooled, filtered and thecrystals are washed, then dried under reduced pressure to giveclopidogrel hydrogen sulfate Form 2.

Another alternative consists of subjecting the crystalline suspension tomechanical shearing with the aid of a shearing device. This device mayattain a speed of rotation of about 10,000 to 15,000 revolutions perminute. Devices equipped with these characteristics are, for example, ofthe Turrax® type sold by IKA-Werke (DE).

Furthermore, these devices are suited to the treatment of industrialquantities.

The principe is to obtain by crushing small particules out of a solutionwhich only contains a part of the sulfuric acid. The remaining part ofacid will then be added slowly to allow crystal growth. Experimentsproceeded starting with the addition of 10% of the amount of thenecessary sulfuric acid.

Thus, the object of the present invention is Form 2 of clopidogrelhydrogen sulfate characterised by the X-ray powder diffraction profilegiven in TABLE I.

More particularly, Form 2 is also characterised by a melting point of176° C., determined by differential enthalpic analysis (DSC) and bycharacteristic absorptions in the infrared and in the near infrared.

Some physical properties and the behaviour of the novel crystalline formof clopidogrel hydrogen sulfate according to the invention arecompletely different from those of Form 1 as was demonstrated byexamining the two forms according to standard methods and procedures.

The X-ray powder diffraction profile (angle of diffraction) wasdetermined with a Siemens D500TT diffractometer. The characteristicpowder diffractograms between 2 and 40° in 2θ (2 theta, deg. , for CuKα,λ=1.542 Å) Bragg angles are shown in FIG. 1 for Form 1 and in FIG. 2 forForm 2. The significant reflections of FIG. 1 are recorded in TABLE IIwhereas those of FIG. 2 are collected in TABLE I. In TABLES I and II, dis the interlattice distance and I/I_(o) represents the relativeintensity, expressed as a percentage of the most intense reflection.

TABLE I Form 2 Significant reflections shown in FIG. 2 d (Å) I/I₀ 4.11100.0 6.86 61.7 3.87 61.4 3.60 56.3 4.80 55.8 5.01 44.4 3.74 37.9 6.4933.1 5.66 29.8

TABLE II Form 1 Significant reflections shown in FIG. 1 d (Å) I/I₀ 9.60100.0 3.49 58.8 3.83 52.0 3.80 42.5 4.31 39.0 8.13 37.2 4.80 25.5 3.8619.1 5.80 16.8 4.95 16.8

The differential enthalpy analysis (DSC) of the Forms 1 and 2 wascarried out comparatively using a Perkin Elmer apparatus DSC7,calibrated by reference to indium. For the calorimetric analysis 2.899mg of Form 1 or 2.574 mg of Form 2 were used, as obtained in EXAMPLE 2,in a crimped and pierced aluminium cup in a temperature range from 40°to 230° C. with a rate of heating of 10° C./minute. The melting pointand the enthalpy of fusion are indicated in TABLE III. The melting pointcorresponds to the characteristic melting temperature obtained by DSC.This value may also be defined as being the temperature corresponding tothe intersection between the baseline and the tangent to the meltingpeak curves observed by DSC.

TABLE III Melting point and enthalpy Form 1 Form 2 Melting point (° C.)181.2 176.0 Enthalpy of fusion (J/g) 77 87

The difference between the new Form 2 and Form 1 of clopidogrel hydrogensulfate has also been demonstrated by infrared spectroscopy. The Fouriertransform (FTIR) IR spectra were obtained with a Perkin Elmer system2000 spectrometer with a resolution of 4 cm⁻¹ from 4000 cm⁻¹ to 400cm⁻¹. The samples of Form 1 or Form 2 are prepared in the form of 0.3%KBr disks. The disks were subjected to a compression of 10 tons for 2minutes. Each sample was examined after 4 accumulated scans.

The comparison of characteristic bands in terms of wavelength (in cm⁻¹)and intensity (as percentage of transmittance) is illustrated in TABLEIV.

TABLE IV Infrared Spectra Form 1 Form 2 Wavelength % Wavelength % (cm⁻¹)transmittance (cm⁻¹) transmittance 2987 42 2551 43   1753 14 1753 13.41222 16 1497 63,7 1175 12 1189 18    841 40 1029 33.2

TABLE IV shows that Form 2 exhibits characteristic absorptions at 2551cm⁻¹, 1497 cm⁻¹, 1189 cm⁻¹ and 1029 cm⁻¹ which are absent from Form 1.

The particular structure of the crystals of Form 2 was elucidated bysingle-crystal X-ray diffraction analysis using a MSC-Rigaka AFC6Sdiffractometer and the software SHELXS-90 and SHELXS-93 at a SG IRISIndigo work station. The position of the C-H hydrogens was generated ata distance of 0.95 Å. The crystallographic data, in particular the unitcells leghts (a, b, c), the angles (α, β, γ) and the volume of each unitcell are shown in TABLE V.

TABLE V Crystallographic data and establishment of the structure of Form2 Crystalline system space group Orthorombic P2₁2₁2₁ Dimensions of unitcell: a 10.321(6) Å b 20.118(9) Å c  9.187(7) Å α 90 degrees β 90degrees γ 90 degrees volume 1908(2) Å³ Z 4 density (calculated) 1.462g/cm³ collected reflexions 2134 R factor 0.0473

The atomic coordinates of Form 2 are given in TABLE VI, the bond lengthsin TABLE VII, the bond angles in TABLE VIII and the characteristicstorsion angles in TABLE IX.

TABLE VI Position parameters of Form 2 atom x y z U(eq) Cl(1) 0.2223(3)0.21728(12) 0.4295(3) 0.0835(8) S(1) 0.8085(2) −0.00068(11) 0.3557(3)0.0724(7) S(2) 0.2840(2) 0.01908(8) 0.0013(2) 0.0412(4) O(1) 0.3030(7)0.2376(3) −0.0528(7) 0.087(2) O(2) 0.4630(6) 0.1637(3) −0.0860(6)0.060(2) O(3) 0.2175(6) −0.0350(3) 0.0957(6) 0.0551(14) O(4) 0.2728(6)−0.0093(3) −0.1432(5) 0.074(2) O(5) 0.4174(4) 0.0241(2) 0.0497(6)0.0503(13) O(6) 0.2146(5) 0.0800(2) 0.0199(7) 0.065(2) N(5) 0.4936(6)0.1343(3) 0.1946(7) 0.0380(14) C(2) 0.9111(10) 0.0427(5) 0.2500(13)0.081(3) C(3A) 0.7214(7) 0.1002(3) 0.2215(9) 0.047(2) C(3) 0.8554(8)0.0950(5) 0.1824(11) 0.060(2) C(4) 0.6332(7) 0.1548(4) 0.1706(10)0.044(2) C(6) 0.4750(8) 0.1100(4) 0.3487(9) 0.045(2) C(7) 0.5487(8)0.0450(4) 0.3722(10) 0.051(2) C(7A) 0.6833(8) 0.0526(3) 0.3144(9)0.050(2) C(8) 0.3940(8) 0.1880(4) 0.1574(9) 0.043(2) C(9) 0.4119(7)0.2523(3) 0.2360(9) 0.044(2) C(10) 0.3435(8) 0.2688(4) 0.3613(10)0.057(2) C(11) 0.3630(10) 0.3292(4) 0.4290(11) 0.076(3) C(12) 0.4545(10)0.3734(4) 0.3773(12) 0.080(3) C(13) 0.5223(10) 0.3579(4) 0.2550(12)0.067(3) C(14) 0.5019(8) 0.2980(3) 0.1863(10) 0.052(2) C(15) 0.3823(8)0.1995(4) −0.0079(11) 0.053(2) C(16) 0.4462(16) 0.1687(6) −0.2422(11)0.096(4)

TABLE VII Intramolecular distances in Form 2 atom atom distance Cl(1)C(10) 1.742(8) S(1) C(2) 1.682(12) S(1) C(7A) 1.722(8) S(2) O(6)1.429(5) S(2) O(4) 1.450(5) S(2) O(5) 1.450(5) S(2) O(3) 1.551(5) O(1)C(15) 1.195(9) O(2) C(15) 1.314(10) O(2) C(16) 1.448(10) N(5) C(6)1.510(10) N(5) C(4) 1.515(9) N(5) C(8) 1.530(9) C(2) C(3) 1.350(13)C(3A) C(7A) 1.341(10) C(3A) C(3) 1.432(10) C(3A) C(4) 1.501(10) C(6)C(7) 1.528(10) C(7) C(7A) 1.495(11) C(8) C(9) 1.493(10) C(8) C(15)1.541(12) C(9) C(14) 1.384(10) C(9) C(10) 1.390(11) C(10) C(11)1.379(11) C(11) C(12) 1.382(12) C(12) C(13) 1.359(13) C(13) C(14)1.378(11)

The distances are in Angstroms. The standard deviations estimated on thelast place of decimals are given in parentheses.

TABLE VIII The intramolecular bond angles between non-hydrogen atomsatom atom atom angle C(2) S(1) C(7A)  91.2(4) O(6) S(2) O(4) 114.0(4)O(6) S(2) O(5) 112.3(3) O(4) S(2) O(5) 112.6(3) O(6) S(2) O(3) 108.2(3)O(4) S(2) O(3) 101.6(3) O(5) S(2) O(3) 107.3(3) C(15) O(2) C(16)115.3(9) C(6) N(5) C(4) 110.1(6) C(6) N(5) C(8) 110.6(6) C(4) N(5) C(8)114.5(5) C(3) C(2) S(1) 113.7(7) C(7A) C(3A) C(3) 113.0(8) C(7A) C(3A)C(4) 122.8(7) C(3) C(3A) C(4) 124.1(8) C(2) C(3) C(3A) 110.7(9) C(3A)C(4) N(5) 109.5(6) N(5) C(6) C(7) 110.2(7) C(7A) C(7) C(6) 108.9(6)C(3A) C(7A) C(7) 124.9(7) C(3A) C(7A) S(1) 111.4(6) C(7) C(7A) S(1)123.7(6) C(9) C(8) N(5) 114.9(6) C(9) C(8) C(15) 110.9(6) N(5) C(8)C(15) 112.2(7) C(14) C(9) C(10) 117.1(7) C(14) C(9) C(8) 119.9(8) C(10)C(9) C(8) 123.0(7) C(11) C(10) C(9) 120.7(8) C(11) C(10) Cl(1) 117.8(7)C(9) C(10) Cl(1) 121.4(6) C(10) C(11) C(12) 120.7(9) C(13) C(12) C(11)119.3(9) C(12) C(13) C(14) 120.0(9) C(13) C(14) C(9) 122.2(9) O(1) C(15)O(2) 126.7(9) O(1) C(15) C(8) 119.3(9) O(2) C(15) C(8) 114.0(7)

The angles are in degrees. The standard deviations estimated on the lastplace of decimals are given in parentheses.

TABLE IX Conformation and characteristic torsion angles (1) (2) (3) (4)angle C(7A) S(1) C(2) C(3) −1.1(9) S(1) C(2) C(3) C(3A) 0.9(12) C(7A)C(3A) C(3) C(2) 0.0(12) C(4) C(3A) C(3) C(2) 177.1(8) C(7A) C(3A) C(4)N(5) −19.7(11) C(3) C(3A) C(4) N(5) 163.4(8) C(6) N(5) C(4) C(3A)50.2(8) C(8) N(5) C(4) C(3A) 175.7(7) C(4) N(5) C(6) C(7) −67.3(8) C(8)N(5) C(6) C(7) 165.0(6) N(5) C(6) C(7) C(7A) 47.8(9) C(3) C(3A) C(7A)C(7) −179.1(8) C(4) C(3A) C(7A) C(7) 3.8(13) C(3) C(3A) C(7A) S(1)−0.8(9) C(4) C(3A) C(7A) S(1) −177.9(6) C(6) C(7) C(7A) C(3A) −17.6(12)C(6) C(7) C(7A) S(1) 164.3(6) C(2) S(1) C(7A) C(3A) 1.1(7) C(2) S(1)C(7A) C(7) 179.4(8) C(6) N(5) C(8) C(9) 68.9(8) C(4) N(5) C(8) C(9)−56.3(10) C(6) N(5) C(8) C(15) −163.2(6) C(4) N(5) C(8) C(15) 71.6(8)N(5) C(8) C(9) C(14) 81.4(9) C(15) C(8) C(9) C(14) −47.2(10) N(5) C(8)C(9) C(10) −97.3(9) C(15) C(8) C(9) C(10) 134.2(8) C(14) C(9) C(10)C(11) 1.9(12) C(8) C(9) C(10) C(11) −179.4(8) C(14) C(9) C(10) Cl(1)176.9(6) C(8) C(9) C(10) Cl(1) −4.4(11) C(9) C(10) C(11) C(12) −2.6(14)Cl(1) C(10) C(11) C(12) −177.8(8) C(10) C(11) C(12) C(13)   3(2) C(11)C(12) C(13) C(14) −2(2) C(12) C(13) C(14) C(9) 1.1(14) C(10) C(9) C(14)C(13) −1.1(12) C(8) C(9) C(14) C(13) −179.9(8) C(16) O(2) C(15) O(1)−4.3(13) C(16) O(2) C(15) C(8) 174.5(8) C(9) C(8) C(15) O(1) −54.0(10)N(5) C(8) C(15) O(1) 176.0(7) C(9) C(8) C(15) O(2) 127.1(7) N(5) C(8)C(15) O(2) −2.8(9)

The angles are in degree. The standard deviations estimated on the lastplace of decimals are given in parentheses.

The sign is positive if, on looking from atom 2 to atom 3, atom 1 issupersposed on atom 4 by a clockwise movement.

The crystallographic study with X rays, in particular thecrystallographic data of TABLE I, the atomic coordinates of TABLE VI,the bond lengths of TABLE VII, the bond angles of TABLE VIII and thecharacteristic torsion angles of TABLE IX prove the structure proposedand illustrated in FIGS. 5 and 6.

The Form 1 crystals are irregular plates and the crystals of Form 2 areagglomerates. Microscopic examination revealed that the crystals of thenew Form 2 are morphologically different from those of Form 1.

As it is less electrostatic than Form 1 it is hence particularly suitedto the manufacture of pharmaceutical compositions for the treatment ofall diseases in which a platelet aggregation inhibitor is indicated.

Thus, according to another of its features, the object of the presentinvention is pharmaceutical compositions containing as active ingredientForm 2 of clopidogrel hydrogen sulfate characterised by the X ray powderdiffraction profile illustrated in TABLE I.

Preferably, Form 2 of clopidogrel hydrogen sulfate according to thepresent invention is formulated in pharmaceutical compositions by theoral route containing 75 mg of active ingredient per dosage unit, in amixture with at least one pharmaceutical excipient.

When a solid composition is prepared in the form of tablets, the mainactive ingredient is mixed with a pharmaceutical vehicle such asgelatin, starch, lactose, magnesium stearate, talc, gum arabic or thelike. The tablets may be coated with sucrose or other suitable materialsor they may also be treated such that they have a prolonged or delayedactivity and so that they continuously release a predefined quantity ofactive ingredient. A preparation of capsules is obtained by mixing theactive ingredient with a diluant and by pouring the mixture obtainedinto soft or hard capsules.

The powders or granules dispersible in water may contain the activeingredient as a mixture with dispersion agents or wetting agents, orsuspending agents like polyvinylpyrrolidone, likewise with sweeteningagents or taste correctors. If it is desired to formulate the activeingredient for rectal administration, recourse is had to suppositorieswhich are prepared with binders melting at the rectal temperature, forexample cocoa butter or polyethyleneglycols.

For parenteral administration, aqueous suspensions, saline solutions orsterile and injectable solutions are used.

The active ingredient may also be formulated in the form ofmicrocapsules, optionally with one or more supports or additives.

The following EXAMPLES illustrate the invention without in any waylimiting it. Preparation of methyl(+)-(S)-α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno-[3,2-c]pyridine-5-acetatecamphorsulfonate

400 kg of racemic methylα-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-acetatehydrochloride and 1840 kg of dichloromethane are loaded into a stirredreactor. Then 1200 kg of an 8% aqueous solution of sodium bicarbonateare added slowly. After decantation, the organic phase is concentratedin a vacuum. The concentrated residue is diluted with 1000 liters ofacetone. A solution of 154 kg of 1 R-10 camphorsulfonic acid in 620liters of acetone is added at 20-25° C. The mixture is cooled and methylα-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-acetatecamphorsulfonate is crystallised by seeding if necessary. Whencrystallisation is abundant, the mixture is heated to reflux, thencooled to 25° C. The crystals are then filtered off and washed withacetone, then dried under reduced pressure. Thus, 196 kg of methyl(+)-(S)-α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-acetatecamphorsulfonate are obtained, i.e. a yield of 33%.

Preparation of Form 2 clopidogrel hydrogen sulfate

EXAMPLE 1A

50 g of clopidogrel camphorsulfate prepared as indicated above isintroduced into a 250 ml reactor under nitrogen. Dichloromethane, 100ml, is added and the mixture is stirred for 10 minutes. Then a solutionof 9.1 g of potassium carbonate dissolved in 70 ml deionized water isintroduced. The organic phase is separated and the aqueous phase iswashed several times with dichloromethane. The organic phases arecombined and concentrated in a vacuum. 229 ml of acetone is added to theconcentrate and the solution is filtered through a 0.1μ to 0.22μ frit.The acetone solution containing the base is loaded into a reactor undernitrogen, and 7.4 g of an 80% sulfuric acid solution is added at 20° C.,then the mixture is heated to reflux; crystallisation starts and refluxis maintained for 2 hours.

The solvent is distilled, the residue is cooled to a temperature of 0 to−5° C. and the crystals are filtered off on a Büchner funnel to obtain21.4 g of Form 2 clopidogrel hydrogen sulfate after drying; m.p.=176±3°C.

EXAMPLE 1B

1200 kg of clopidogrel camphorsulfate prepared as indicated above isintroduced into a 6000 l reactor under nitrogen. Dichloromethane, 2345l, is added and the mixture is stirred for 30 minutes to 1 hour. Then asolution of 214.5 kg of potassium carbonate dissolved in 1827 ldeionized water is introduced. The organic phase is separated and theaqueous phase is washed several times with dichloromethane. The organicphases are combined and concentrated in a vacuum. Acetone is added tothe concentrate and the solution is filtered through a 0.1μ to 1μfiltration cartdridge. The acetone solution (3033 l) containing the baseis loaded into a reactor under nitrogen, and 264.8 kg of an 80% sulfuricacid solution is added at 20° C.

The solvent is distilled, the residue is cooled to a temperature of 0 to−5° C. and the crystals are filtered off on a Büchner funnel to obtain779.1 kg of Form 1 clopidogrel hydrogen sulfate after drying;m.p.=184±3° C.

The resulting mother liquors, at a temperature bellow 40° C., yieldafter a 3 to 6 months period crystals of clopidogrel hydrogen sulfateForm 2; m.p.=176±3° C.

EXAMPLE 1C

1200 kg of clopidogrel camphorsulfate prepared as indicated above isintroduced into a 6000 l reactor under nitrogen. Dichloromethane, 2345l, is added and the mixture is stirred for 30 minutes to 1 hour. Then asolution of 214.5 kg of potassium carbonate dissolved in 1827 ldeionized water is introduced. The organic phase is separated and theaqueous phase is washed several times with dichloromethane. The organicphases are combined and concentrated in a vacuum. Acetone is added tothe concentrate and the solution is filtered through a 0.1μ to 1μfiltration cartdridge. The acetone solution (3033 l) containing the baseis loaded into a reactor under nitrogen, and 264.8 kg of an 96% sulfuricacid solution is added at 20° C.

The solvent is distilled, the residue is cooled to a temperature of 0 to−5° C. and the crystals are filtered off on a Büchner funnel to obtain785.3 kg of Form 1 clopidogrel hydrogen sulfate after drying;m.p.=184±3° C.

The resulting mother liquors, at a temperature bellow 40° C., yieldafter a 3 to 6 months period crystals of clopidogrel hydrogen sulfateForm 2; m.p.=176±3° C.

EXAMPLE 2

Dichloromethane, 909 l, and 450 kg of methyl(+)-(S)-α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-acetatecamphorsulfonate are loaded into a reactor. The camphorsulfonic acid isextracted by means of an aqueous solution of 80 kg of potassiumcarbonate in 680 l of water. The organic phase is then washed withwater. The dichloromethane is concentrated and the concentrated residueis taken up in 1140 liters of acetone. Then, 100 kg of 96% sulfuric acidis added at 20° C. Seeding is performed with 0.3 kg of clopidogrelhydrogen sulfate Form 2 obtained in EXAMPLE 1B or 1C. Clopidogrelhydrogen sulfate crystallises. It is filtered off, washed with acetoneand dried under reduced pressure. Clopidogrel hydrogen sulfate Form 2,310 kg, is obtained, i.e. a yield of 90.9%; m.p.=176±3° C.

EXAMPLE 3

Dichloromethane, 909 l, and 450 kg of methyl(+)-(S)-α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-acetatecamphorsulfonate are loaded into a reactor. The camphorsulfonic acid isextracted by means of an aqueous solution of 80 kg of potassiumcarbonate in 680 l of water. The organic phase is then washed withwater. The dichloromethane is concentrated and the concentrated residueis taken up in 1296 liters of acetone.

The temperature is then stabilised at 20° C. and the Turrax® is set intoaction. 10% of the global amount of 94-96% sulfuric acid (8.3 kg) isthen added in a few minutes. Then 0.012 kg of clopidogrel hydrogensulfate Form 2 obtain according to examples 1B or 1C are used forseeding. Clopidogrel hydrogen sulfate Form 2 crystallises. The mixtureis left for 45 minutes under the action of Turrax®. The 90% of sulfuricacid at 94-96% (74.6 kg) are then added within 2 hours while Turrax® isstill acting. Turrax® is stopped 30 minutes after the acid addition. Themixture is then stirred for 30 minutes at 20° C., filtered, wash withacetone and dried under vacuo.

Then 310 kg of clopidogrel hydrogen sulfate Form 2 are obtained, yield90.9%; F=176±3° C.

What is claimed is:
 1. A crystalline polymorph of (+)-(S) clopidogrelhydrogen sulfate (Form 2), the X ray powder diffractogram of which showscharacteristic peaks expressed as interplanar distance at approximately4.11; 6.86; 3.60; 5.01; 3.74; 6.49 and 5.66 Å.
 2. A crystallinepolymorph of (+)-(S) clopidogrel hydrogen sulfate (Form 2), the infraredspectrum of which exhibits characteristic absorptions expressed in cm⁻¹at 2551, 1497, 1189 and 1029, with respective transmittance percentagesof approximately 43; 63.7; 18 and 33.2.
 3. A crystalline polymorph of(+)-(S) clopidogrel hydrogen sulfate (Form 2) having a melting point of176+/−3° C.
 4. A crystalline polymorph of clopidogrel hydrogen sulfate(Form 2) exhibiting the X ray powder diffractogram of FIG.
 2. 5. Acrystalline polymorph of clopidogrel hydrogen sulfate (Form 2)exhibiting the infrared spectrum of FIG.
 3. 6. A crystalline polymorphof clopidogrel hydrogen sulfate (Form 2) exhibiting the X ray powderdiffractogram which shows characteristic peaks expressed as interplanardistance at approximately 4.11; 6.86; 3.60; 5.01; 3.74; 6.49 and 5.66 Åand an infrared spectrum which shows characteristic absorptionsexpressed in cm⁻¹ at 2551, 1497, 1189 and 1029, with respectivetransmittance percentages of approximately 43, 63.7, 18 and 33.2.
 7. Apharmaceutical composition comprising an effective amount of thepolymorph Form 2 of clopidogrel hydrogen sulfate according to claim 1 incombination with at least one pharmaceutical excipient.
 8. (+)-(S)Clopidogrel hydrogen sulfate, the x-ray powder diffraction pattern ofwhich shows a characteristic peak, expressed in terms of interplanardistance, at approximately 4.11 Å.
 9. (+)-(S) Clopidogrel hydrogensulfate, the x-ray powder diffraction pattern of which shows acharacteristic peak, expressed in terms of interplanar distance, atapproximately 6.86 Å.
 10. (+)-(S) Clopidogrel hydrogen sulfate, thex-ray powder diffraction pattern of which shows a characteristic peak,expressed in terms of interplanar distance, at approximately 3.60 Å. 11.(+)-(S) Clopidogrel hydrogen sulfate, the x-ray powder diffractionpattern of which shows a characteristic peak, expressed in terms ofinterplanar distance, at approximately 3.87 Å.
 12. (+)-(S) Clopidogrelhydrogen sulfate according to claim 8 wherein the x-ray powderdiffraction pattern further shows a characteristic peak at approximately6.86 Å.
 13. (+)-(S) Clopidogrel hydrogen sulfate according to claim 12wherein the x-ray powder diffraction pattern further shows acharacteristic peak at approximately 3.60 Å.
 14. (+)-(S) Clopidogrelhydrogen sulfate according to claim 9 wherein the x-ray powderdiffraction pattern further shows a characteristic peak at approximately3.60 Å.
 15. (+)-(S) Clopidogrel hydrogen sulfate having an enthalpy offusion of 87 J/g.